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1
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Ciernikova S, Sevcikova A, Mego M. Targeting the gut and tumor microbiome in cancer treatment resistance. Am J Physiol Cell Physiol 2024; 327:C1433-C1450. [PMID: 39437444 DOI: 10.1152/ajpcell.00201.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 10/18/2024] [Accepted: 10/18/2024] [Indexed: 10/25/2024]
Abstract
Therapy resistance represents a significant challenge in oncology, occurring in various therapeutic approaches. Recently, animal models and an increasing set of clinical trials highlight the crucial impact of the gut and tumor microbiome on treatment response. The intestinal microbiome contributes to cancer initiation, progression, and formation of distant metastasis. In addition, tumor-associated microbiota is considered a critical player in influencing tumor microenvironments and regulating local immune processes. Intriguingly, numerous studies have successfully identified pathogens within the gut and tumor microbiome that might be linked to a poor response to different therapeutic modalities. The unfavorable microbial composition with the presence of specific microbes participates in cancer resistance and progression via several mechanisms, including upregulation of oncogenic pathways, macrophage polarization reprogramming, metabolism of chemotherapeutic compounds, autophagy pathway modulation, enhanced DNA damage repair, inactivation of a proapoptotic cascade, and bacterial secretion of extracellular vesicles, promoting the processes in the metastatic cascade. Targeted elimination of specific intratumoral bacteria appears to enhance treatment response. However, broad-spectrum antibiotic pretreatment is mostly connected to reduced efficacy due to gut dysbiosis and lower diversity. Mounting evidence supports the potential of microbiota modulation by probiotics and fecal microbiota transplantation to improve intestinal dysbiosis and increase microbial diversity, leading to enhanced treatment efficacy while mitigating adverse effects. In this context, further research concerning the identification of clinically relevant microbiome signatures followed by microbiota-targeted strategies presents a promising approach to overcoming immunotherapy and chemotherapy resistance in refractory patients, improving their outcomes.
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Affiliation(s)
- Sona Ciernikova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Aneta Sevcikova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Michal Mego
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
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2
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Chen Z, Guan D, Wang Z, Li X, Dong S, Huang J, Zhou W. Microbiota in cancer: molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2023; 4:e417. [PMID: 37937304 PMCID: PMC10626288 DOI: 10.1002/mco2.417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 10/04/2023] [Accepted: 10/12/2023] [Indexed: 11/09/2023] Open
Abstract
The diverse bacterial populations within the symbiotic microbiota play a pivotal role in both health and disease. Microbiota modulates critical aspects of tumor biology including cell proliferation, invasion, and metastasis. This regulation occurs through mechanisms like enhancing genomic damage, hindering gene repair, activating aberrant cell signaling pathways, influencing tumor cell metabolism, promoting revascularization, and remodeling the tumor immune microenvironment. These microbiota-mediated effects significantly impact overall survival and the recurrence of tumors after surgery by affecting the efficacy of chemoradiotherapy. Moreover, leveraging the microbiota for the development of biovectors, probiotics, prebiotics, and synbiotics, in addition to utilizing antibiotics, dietary adjustments, defensins, oncolytic virotherapy, and fecal microbiota transplantation, offers promising alternatives for cancer treatment. Nonetheless, due to the extensive and diverse nature of the microbiota, along with tumor heterogeneity, the molecular mechanisms underlying the role of microbiota in cancer remain a subject of intense debate. In this context, we refocus on various cancers, delving into the molecular signaling pathways associated with the microbiota and its derivatives, the reshaping of the tumor microenvironmental matrix, and the impact on tolerance to tumor treatments such as chemotherapy and radiotherapy. This exploration aims to shed light on novel perspectives and potential applications in the field.
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Affiliation(s)
- Zhou Chen
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Defeng Guan
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Zhengfeng Wang
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Xin Li
- The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The Department of General SurgeryLanzhou University Second HospitalLanzhouGansuChina
| | - Shi Dong
- The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The Department of General SurgeryLanzhou University Second HospitalLanzhouGansuChina
| | - Junjun Huang
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Wence Zhou
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The Department of General SurgeryLanzhou University Second HospitalLanzhouGansuChina
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3
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Galyamina MA, Pobeguts OV, Gorbachev AY. The role of mycoplasmas as an infectious agent in carcinogenesis. ADVANCES IN MOLECULAR ONCOLOGY 2023; 10:36-49. [DOI: 10.17650/2313-805x-2023-10-3-36-49] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The review presents data on studies of the role of mycoplasmas as infectious agents in carcinogenesis, as well as their participation in cancer drug therapy and the impact on the outcome of treatment. Mycoplasmas are of particular interest because they have unique abilities to readily attach to and enter eukaryotic cells, modulate their functional state, and induce chronic inflammation while evading the host’s immune system. The review will highlight the data confirming the increased colonization of tumor tissue by mycoplasmas compared to healthy ones, describe the molecular mechanisms by which mycoplasmas activate the expression of oncogenes and growth factors, inactivate tumor suppressors, promote NF-κB-dependent migration of cancer cells and modulate apoptosis, which results in abnormal growth and transformation of host cells. The review also presents data on the effectiveness of anticancer drugs in mycoplasmal infections.
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Affiliation(s)
- M. A. Galyamina
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency
| | - O. V. Pobeguts
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency
| | - A. Yu. Gorbachev
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency
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4
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Algrafi AS, Jamal AA, Ismaeel DM. Microbiota as a New Target in Cancer Pathogenesis and Treatment. Cureus 2023; 15:e47072. [PMID: 38021696 PMCID: PMC10645418 DOI: 10.7759/cureus.47072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2023] [Indexed: 12/01/2023] Open
Abstract
The microbial ecosystem of humans is an integral part of human health and disease. A significant percentage of tumors worldwide are thought to be microbially induced. The relationship between cancer and microbes is complex. In this article review, we aim to give an overview of human microbiota and its role in carcinogenesis, emphasize the relation between microbiota and cancer immunity, and highlight its role in the future of cancer therapy. The term microbiota refers to the collection of microorganisms that are located in an individual, whereas the total genome of these microorganisms is referred to as the microbiome. The microbiota in humans has many physiological functions. The microbiota within the gut lumen has a profound effect on the local and systemic immune system. The immune system can change the gut microbiota. Microbiota may induce carcinogenesis by several mechanisms. It also affects tumor progression. Thus, microbiota modulation may aid in the prevention and treatment of cancer. Intentionally introducing microorganisms into the oncological patient is assumed to mobilize the immune system to become able to, at least, limit the development of cancer. Microbes are used as vectors which are carriers of particular antineoplastic agents that reduce the side effects of chemotherapy. Inflammation and tumor microenvironment play an essential role in promoting chemo-resistance. There is now considerable evidence, both in humans as well as in laboratory animals, that the commensal microbiota has important effects on carcinogenesis, tumor growth, and therapy response.
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Affiliation(s)
- Abeer S Algrafi
- Internal Medicine, College of Medicine, Taibah University, Madinah, SAU
| | - Aisha A Jamal
- General Practice, College of Medicine, Taibah University, Madinah, SAU
| | - Dana M Ismaeel
- General Practice, College of Medicine, Taibah University, Madinah, SAU
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5
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Han H, Xing L, Chen BT, Liu Y, Zhou TJ, Wang Y, Zhang LF, Li L, Cho CS, Jiang HL. Progress on the pathological tissue microenvironment barrier-modulated nanomedicine. Adv Drug Deliv Rev 2023; 200:115051. [PMID: 37549848 DOI: 10.1016/j.addr.2023.115051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 07/21/2023] [Accepted: 08/04/2023] [Indexed: 08/09/2023]
Abstract
Imbalance in the tissue microenvironment is the main obstacle to drug delivery and distribution in the human body. Before penetrating the pathological tissue microenvironment to the target site, therapeutic agents are usually accompanied by three consumption steps: the first step is tissue physical barriers for prevention of their penetration, the second step is inactivation of them by biological molecules, and the third step is a cytoprotective mechanism for preventing them from functioning on specific subcellular organelles. However, recent studies in drug-hindering mainly focus on normal physiological rather than pathological microenvironment, and the repair of damaged physiological barriers is also rarely discussed. Actually, both the modulation of pathological barriers and the repair of damaged physiological barriers are essential in the disease treatment and the homeostasis maintenance. In this review, we present an overview describing the latest advances in the generality of these pathological barriers and barrier-modulated nanomedicine. Overall, this review holds considerable significance for guiding the design of nanomedicine to increase drug efficacy in the future.
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Affiliation(s)
- Han Han
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Lei Xing
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; College of Pharmacy, Yanbian University, Yanji 133002, China
| | - Bi-Te Chen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Yang Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Tian-Jiao Zhou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Yi Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Ling-Feng Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
| | - Chong-Su Cho
- Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea.
| | - Hu-Lin Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; College of Pharmacy, Yanbian University, Yanji 133002, China.
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6
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Bahuguna A, Dubey SK. Relevance of tumor microbiome in cancer incidence, prognosis, and its clinical implications in therapeutics. Biochim Biophys Acta Rev Cancer 2023; 1878:188956. [PMID: 37473857 DOI: 10.1016/j.bbcan.2023.188956] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/07/2023] [Accepted: 07/13/2023] [Indexed: 07/22/2023]
Abstract
The microbiota is garnering progressively greater consideration as an essential facet of the tumor microenvironment that regulates tumor proliferation and affects cancer prognosis. Microbial populations that inhabit different body locations are involved in the carcinogenesis and tumor progression of their corresponding malignancies. It has been learned that the microbial populations primarily thriving within tumors are tumor-type specific. Mechanistic studies have revealed that the tumor-associated microbiota contributes to playing a pivotal role in the establishment of the tumor microenvironment, regulation of local immunity, modulation of tumor cell biology, and directly influences the therapeutic efficacy of drug treatment for tumors. This review article incorporates the pertinent studies on recent advancements in tumor microbiome studies, the interplay between the intratumor microbiota and cancer, and, discusses their role and mechanism of action in the emergence and treatment of cancer, and their relationship to clinical characteristics.
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Affiliation(s)
- Ananya Bahuguna
- Department of Biochemistry, College of Basic Sciences and Humanities, Govind Ballabh Pant University of Agriculture and Technology, Pantnagar 263145, Uttarakhand, India
| | - Shiv Kumar Dubey
- Department of Biochemistry, College of Basic Sciences and Humanities, Govind Ballabh Pant University of Agriculture and Technology, Pantnagar 263145, Uttarakhand, India.
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7
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Malhotra P, Palanisamy R, Caparros-Martin JA, Falasca M. Bile Acids and Microbiota Interplay in Pancreatic Cancer. Cancers (Basel) 2023; 15:3573. [PMID: 37509236 PMCID: PMC10377396 DOI: 10.3390/cancers15143573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open
Abstract
Evidence suggests the involvement of the microbiota, including oral, intra-tumoral and gut, in pancreatic cancer progression and response to therapy. The gut microbiota modulates the bile acid pool and is associated with maintaining host physiology. Studies have shown that the bile acid/gut microbiota axis is dysregulated in pancreatic cancer. Bile acid receptor expression and bile acid levels are dysregulated in pancreatic cancer as well. Studies have also shown that bile acids can cause pancreatic cell injury and facilitate cancer cell proliferation. The microbiota and its metabolites, including bile acids, are also altered in other conditions considered risk factors for pancreatic cancer development and can alter responses to chemotherapeutic treatments, thus affecting patient outcomes. Altogether, these findings suggest that the gut microbial and/or bile acid profiles could also serve as biomarkers for pancreatic cancer detection. This review will discuss the current knowledge on the interaction between gut microbiota interaction and bile acid metabolism in pancreatic cancer.
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Affiliation(s)
- Pratibha Malhotra
- Metabolic Signalling Group, Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia
| | - Ranjith Palanisamy
- Metabolic Signalling Group, Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia
| | | | - Marco Falasca
- Metabolic Signalling Group, Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia
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8
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Schepis T, De Lucia SS, Pellegrino A, Del Gaudio A, Maresca R, Coppola G, Chiappetta MF, Gasbarrini A, Franceschi F, Candelli M, Nista EC. State-of-the-Art and Upcoming Innovations in Pancreatic Cancer Care: A Step Forward to Precision Medicine. Cancers (Basel) 2023; 15:3423. [PMID: 37444534 DOI: 10.3390/cancers15133423] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/20/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Pancreatic cancer remains a social and medical burden despite the tremendous advances that medicine has made in the last two decades. The incidence of pancreatic cancer is increasing, and it continues to be associated with high mortality and morbidity rates. The difficulty of early diagnosis (the lack of specific symptoms and biomarkers at early stages), the aggressiveness of the disease, and its resistance to systemic therapies are the main factors for the poor prognosis of pancreatic cancer. The only curative treatment for pancreatic cancer is surgery, but the vast majority of patients with pancreatic cancer have advanced disease at the time of diagnosis. Pancreatic surgery is among the most challenging surgical procedures, but recent improvements in surgical techniques, careful patient selection, and the availability of minimally invasive techniques (e.g., robotic surgery) have dramatically reduced the morbidity and mortality associated with pancreatic surgery. Patients who are not candidates for surgery may benefit from locoregional and systemic therapy. In some cases (e.g., patients for whom marginal resection is feasible), systemic therapy may be considered a bridge to surgery to allow downstaging of the cancer; in other cases (e.g., metastatic disease), systemic therapy is considered the standard approach with the goal of prolonging patient survival. The complexity of patients with pancreatic cancer requires a personalized and multidisciplinary approach to choose the best treatment for each clinical situation. The aim of this article is to provide a literature review of the available treatments for the different stages of pancreatic cancer.
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Affiliation(s)
- Tommaso Schepis
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Sara Sofia De Lucia
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Antonio Pellegrino
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Angelo Del Gaudio
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Rossella Maresca
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Gaetano Coppola
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Michele Francesco Chiappetta
- Section of Gastroenterology and Hepatology, Promise, Policlinico Universitario Paolo Giaccone, 90127 Palermo, Italy
- IBD-Unit, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
| | - Antonio Gasbarrini
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Francesco Franceschi
- Department of Emergency Anesthesiological and Reanimation Sciences, Fondazione Universitaria Policlinico Agostino Gemelli di Roma, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Marcello Candelli
- Department of Emergency Anesthesiological and Reanimation Sciences, Fondazione Universitaria Policlinico Agostino Gemelli di Roma, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Enrico Celestino Nista
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
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9
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Goubet AG. Could the tumor-associated microbiota be the new multi-faceted player in the tumor microenvironment? Front Oncol 2023; 13:1185163. [PMID: 37287916 PMCID: PMC10242102 DOI: 10.3389/fonc.2023.1185163] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 05/02/2023] [Indexed: 06/09/2023] Open
Abstract
Microorganisms have been identified in tumor specimens for over a century. It is only in recent years that tumor-associated microbiota has become a rapidly expanding field. Assessment techniques encompass methods at the frontiers of molecular biology, microbiology, and histology, requiring a transdisciplinary process to carefully decipher this new component of the tumor microenvironment. Due to the low biomass, the study of tumor-associated microbiota poses technical, analytical, biological, and clinical challenges and must be approached as a whole. To date, several studies have begun to shed light on the composition, functions, and clinical relevance of the tumor-associated microbiota. This new piece of the tumor microenvironment puzzle could potentially change the way we think about and treat patients with cancer.
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Affiliation(s)
- Anne-Gaëlle Goubet
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- AGORA Cancer Research Center, Lausanne, Switzerland
- Swiss Cancer Center Léman, Lausanne, Switzerland
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Ojala T, Kankuri E, Kankainen M. Understanding human health through metatranscriptomics. Trends Mol Med 2023; 29:376-389. [PMID: 36842848 DOI: 10.1016/j.molmed.2023.02.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 02/02/2023] [Accepted: 02/08/2023] [Indexed: 02/27/2023]
Abstract
Metatranscriptomics has revolutionized our ability to explore and understand transcriptional programs in microbial communities. Moreover, it has enabled us to gain deeper and more specific insight into the microbial activities in human gut, respiratory, oral, and vaginal communities. Perhaps the most important contribution of metatranscriptomics arises, however, from the analyses of disease-associated communities. We review the advantages and disadvantages of metatranscriptomics analyses in understanding human health and disease. We focus on human tissues low in microbial biomass and conditions associated with dysbiotic microbiota. We conclude that a more widespread use of metatranscriptomics and increased knowledge on microbe activities will uncover critical interactions between microbes and host in human health and provide diagnostic basis for culturing-independent, direct functional pathogen identification.
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Affiliation(s)
- Teija Ojala
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Laboratory of Genetics, HUS Diagnostic Center, Hospital District of Helsinki and Uusimaa (HUS), Helsinki, Finland
| | - Esko Kankuri
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Matti Kankainen
- Laboratory of Genetics, HUS Diagnostic Center, Hospital District of Helsinki and Uusimaa (HUS), Helsinki, Finland; Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland.
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11
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Chrysostomou D, Roberts LA, Marchesi JR, Kinross JM. Gut Microbiota Modulation of Efficacy and Toxicity of Cancer Chemotherapy and Immunotherapy. Gastroenterology 2023; 164:198-213. [PMID: 36309208 DOI: 10.1053/j.gastro.2022.10.018] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 10/02/2022] [Accepted: 10/16/2022] [Indexed: 01/31/2023]
Abstract
Accumulating evidence supports not only the functional role of the gut microbiome in cancer development and progression but also its role in defining the efficacy and toxicity of chemotherapeutic agents (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and immunotherapeutic compounds (anti-programmed death-ligand 1/anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte-associated antigen 4). This evidence is supported in numerous in vitro, animal, and clinical studies that highlight the importance of microbial mechanisms in defining therapeutic responses. The microbiome therefore shapes oncologic outcomes and is now being leveraged for the development of novel personalized therapeutic approaches in cancer treatment. However, if the microbiome is to be successfully translated into next-generation oncologic treatments, a new multimodal model of the oncomicrobiome must be conceptualized that incorporates gut microbial cometabolism of pharmacologic agents into cancer care. The objective of this review is therefore to outline the current knowledge of oncologic pharmacomicrobiomics and to describe how the multiparametric functions of the gut microbiome influence treatment response across cancer types. The secondary objective is to propose innovative approaches for modulating the gut microbiome in clinical environments that improve therapy efficacy and diminish toxic effects derived from antineoplastic agents for patient benefit.
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Affiliation(s)
- Despoina Chrysostomou
- Centre for Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Lauren A Roberts
- Centre for Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Julian R Marchesi
- Centre for Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - James M Kinross
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
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12
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Nista EC, Del Gaudio A, Del Vecchio LE, Mezza T, Pignataro G, Piccioni A, Gasbarrini A, Franceschi F, Candelli M. Pancreatic Cancer Resistance to Treatment: The Role of Microbiota. Biomedicines 2023; 11:biomedicines11010157. [PMID: 36672664 PMCID: PMC9856157 DOI: 10.3390/biomedicines11010157] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/30/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Pancreatic cancer (PC) is an aggressive malignancy and the fourth leading cause of cancer death in the United States and Europe. It is estimated that PC will be the second leading cause of cancer death by 2030. In addition to late diagnosis, treatment resistance is a major cause of shortened survival in pancreatic cancer. In this context, there is growing evidence that microbes play a regulatory role, particularly in therapy resistance and in creating a microenvironment in the tumor, that favors cancer progression. The presence of certain bacteria belonging to the gamma-proteobacteria or mycoplasmas appears to be associated with both pharmacokinetic and pharmacodynamic changes. Recent evidence suggests that the microbiota may also play a role in resistance mechanisms to immunotherapy and radiotherapy. However, the interactions between microbiota and therapy are bilateral and modulate therapy tolerance. Future perspectives are increasingly focused on elucidating the role of the microbiota in tumorigenesis and processes of therapy resistance, and a better understanding of these mechanisms may provide important opportunities to improve survival in these patients.
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Affiliation(s)
- Enrico Celestino Nista
- Medical and Surgical Science Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Angelo Del Gaudio
- Medical and Surgical Science Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Livio Enrico Del Vecchio
- Medical and Surgical Science Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Teresa Mezza
- Medical and Surgical Science Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Giulia Pignataro
- Emergency Medicine Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Andrea Piccioni
- Emergency Medicine Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Medical and Surgical Science Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesco Franceschi
- Emergency Medicine Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Marcello Candelli
- Emergency Medicine Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence: ; Tel.: +0039-063-0153-188
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13
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Eistrikh-Heller PA, Rubinsky SV, Samygina VR, Lashkov AA. Calculation of Free Energy of Binding for Widely Specific Pyrimidine-Nucleoside Phosphorylase and Suspected Inhibitors. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2022. [DOI: 10.1134/s1068162022060103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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14
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Panebianco C, Ciardiello D, Villani A, Maiorano BA, Latiano TP, Maiello E, Perri F, Pazienza V. Insights into the role of gut and intratumor microbiota in pancreatic ductal adenocarcinoma as new key players in preventive, diagnostic and therapeutic perspective. Semin Cancer Biol 2022; 86:997-1007. [PMID: 34838957 DOI: 10.1016/j.semcancer.2021.11.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/18/2021] [Accepted: 11/24/2021] [Indexed: 02/08/2023]
Abstract
Microbiota consists of a dynamic organization of bacteria, viruses, archaea, and fungal species involved in a number of vital functions spanning from the digestion of carbohydrates, vitamin synthesis, involvement in immune system to drug metabolism. More than 95 % of microbiota resides within the gut and it is essential for maintaining gut homeostasis. Dysregulation of gut microbiota contributes to the onset of several non-communicable diseases including cancer. Among the latter, pancreatic cancer is catching the attention of scientists around the globe being one of the most aggressive and resistant to therapies positioning the pancreatic cancer as one of the leading causes of death from cancer worldwide. In recent years, several studies have shown that the gut and tumor microbiota play a key role in the development, progression and prognosis of PDAC, mainly due to microbial ability to modulate host immune system and metabolize drugs. This review will focus on the new insights into the role of the microbiota as a new key player in pancreatic cancer PDAC development and prognosis by enlightening the microbial potential to interact with chemo/immunotherapeutic drugs and to modulate tumor microenvironment, thus impacting on cancer therapy success with the aim to pave the way to new integrative and interventional diagnostics or therapeutics approaches to prevent, diagnose and treat pancreatic cancer.
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Affiliation(s)
- Concetta Panebianco
- Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Davide Ciardiello
- Oncology Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Oncology Unit, Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Annacandida Villani
- Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Brigida Anna Maiorano
- Oncology Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Department of Translational Medicine and Surgery, Catholic University of Sacred Heart, Rome, Italy
| | - Tiziana Pia Latiano
- Oncology Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Evaristo Maiello
- Oncology Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Francesco Perri
- Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Valerio Pazienza
- Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
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15
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Chifiriuc MC, Filip R, Constantin M, Pircalabioru GG, Bleotu C, Burlibasa L, Ionica E, Corcionivoschi N, Mihaescu G. Common themes in antimicrobial and anticancer drug resistance. Front Microbiol 2022; 13:960693. [PMID: 36003940 PMCID: PMC9393787 DOI: 10.3389/fmicb.2022.960693] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 07/22/2022] [Indexed: 11/13/2022] Open
Abstract
Antimicrobial and anticancer drug resistance represent two of the main global challenges for the public health, requiring immediate practical solutions. In line with this, we need a better understanding of the origins of drug resistance in prokaryotic and eukaryotic cells and the evolutionary processes leading to the occurrence of adaptive phenotypes in response to the selective pressure of therapeutic agents. The purpose of this paper is to present some of the analogies between the antimicrobial and anticancer drug resistance. Antimicrobial and anticancer drugs share common targets and mechanisms of action as well as similar mechanisms of resistance (e.g., increased drug efflux, drug inactivation, target alteration, persister cells’ selection, protection of bacterial communities/malignant tissue by an extracellular matrix, etc.). Both individual and collective stress responses triggered by the chemotherapeutic agent involving complex intercellular communication processes, as well as with the surrounding microenvironment, will be considered. The common themes in antimicrobial and anticancer drug resistance recommend the utility of bacterial experimental models for unraveling the mechanisms that facilitate the evolution and adaptation of malignant cells to antineoplastic drugs.
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Affiliation(s)
- Mariana Carmen Chifiriuc
- Faculty of Biology, University of Bucharest, Bucharest, Romania
- Life, Environmental and Earth Sciences Division, Research Institute of the University of Bucharest, Bucharest, Romania
- The Romanian Academy, Bucharest, Romania
- Academy of Romanian Scientists, Bucharest, Romania
| | - Roxana Filip
- Faculty of Medicine and Biological Sciences, Stefan cel Mare University of Suceava, Suceava, Romania
- Suceava Emergency County Hospital, Suceava, Romania
| | | | - Gratiela Gradisteanu Pircalabioru
- Faculty of Biology, University of Bucharest, Bucharest, Romania
- Academy of Romanian Scientists, Bucharest, Romania
- *Correspondence: Gratiela Gradisteanu Pircalabioru,
| | - Coralia Bleotu
- Stefan S. Nicolau Institute of Virology, Bucharest, Romania
- Romanian Academy of Scientists, Bucharest, Romania
- Coralia Bleotu, ;
| | | | - Elena Ionica
- Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Nicolae Corcionivoschi
- Bacteriology Branch, Veterinary Sciences Division, Agri-Food and Biosciences Institute, Belfast, United Kingdom
- Faculty of Bioengineering of Animal Resources, Banat University of Agricultural Sciences and Veterinary Medicine—King Michael I of Romania, Timisoara, Romania
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16
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Unlocking the Potential of the Human Microbiome for Identifying Disease Diagnostic Biomarkers. Diagnostics (Basel) 2022; 12:diagnostics12071742. [PMID: 35885645 PMCID: PMC9315466 DOI: 10.3390/diagnostics12071742] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/10/2022] [Accepted: 07/14/2022] [Indexed: 02/07/2023] Open
Abstract
The human microbiome encodes more than three million genes, outnumbering human genes by more than 100 times, while microbial cells in the human microbiota outnumber human cells by 10 times. Thus, the human microbiota and related microbiome constitute a vast source for identifying disease biomarkers and therapeutic drug targets. Herein, we review the evidence backing the exploitation of the human microbiome for identifying diagnostic biomarkers for human disease. We describe the importance of the human microbiome in health and disease and detail the use of the human microbiome and microbiota metabolites as potential diagnostic biomarkers for multiple diseases, including cancer, as well as inflammatory, neurological, and metabolic diseases. Thus, the human microbiota has enormous potential to pave the road for a new era in biomarker research for diagnostic and therapeutic purposes. The scientific community needs to collaborate to overcome current challenges in microbiome research concerning the lack of standardization of research methods and the lack of understanding of causal relationships between microbiota and human disease.
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17
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Xie Y, Xie F, Zhou X, Zhang L, Yang B, Huang J, Wang F, Yan H, Zeng L, Zhang L, Zhou F. Microbiota in Tumors: From Understanding to Application. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200470. [PMID: 35603968 PMCID: PMC9313476 DOI: 10.1002/advs.202200470] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 04/30/2022] [Indexed: 05/09/2023]
Abstract
Microbes with complex functions have been found to be a potential component in tumor microenvironments. Due to their low biomass and other obstacles, intratumor microbiota is poorly understood. Mucosal sites and normal adjacent tissues are important sources of intratumor microbiota, while hematogenous spread also leads to the invasion of microbes. Intratumor microbiota affects the progression of tumors through several mechanisms, such as DNA damage, activation of oncogenic pathways, induction of immunosuppression, and metabolization of drugs. Notably, in different types of tumors, the composition and abundance of intratumor microbiota are highly heterogeneous and may play different roles in the progression of tumors. Because of the concern in this field, several techniques such as omics and immunological methods have been used to study intratumor microbiota. Here, recent progress in this field is reviewed, including the potential sources of intratumor microbiota, their functions and related mechanisms, and their heterogeneity. Techniques that can be used to study intratumor microbiota are also discussed. Moreover, research is summarized into the development of strategies that can be used in antitumor treatment and prospects for possible future research in this field.
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Affiliation(s)
- Yifan Xie
- School of MedicineZhejiang University City CollegeSuzhou215123P. R. China
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Feng Xie
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123P. R. China
| | - Xiaoxue Zhou
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Lei Zhang
- Department of Orthopaedic Surgery WenzhouThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou32500P. R. China
| | - Bing Yang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Jun Huang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Fangwei Wang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Haiyan Yan
- School of MedicineZhejiang University City CollegeSuzhou215123P. R. China
| | - Linghui Zeng
- School of MedicineZhejiang University City CollegeSuzhou215123P. R. China
| | - Long Zhang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Fangfang Zhou
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123P. R. China
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18
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Ma Y, Liu X, Wang J. Small molecules in the big picture of gut microbiome-host cross-talk. EBioMedicine 2022; 81:104085. [PMID: 35636316 PMCID: PMC9156878 DOI: 10.1016/j.ebiom.2022.104085] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/06/2022] [Accepted: 05/13/2022] [Indexed: 12/12/2022] Open
Abstract
Research on the gut microbiome and related diseases is rapidly growing with the development of sequencing technologies. An increasing number of studies offer new perspectives on disease development or treatment. Among these, the mechanisms of gut microbial metabolite-mediated effects merit better understanding. In this review, we first summarize the shifts in gut microbial metabolites within complex diseases, in which metabolites have correlational and occasionally causal effects on diseases and discuss the reported mechanisms. We further investigate the interactions between gut microbes and drugs, providing insights for precision medication as well as limitations of current research. Finally, we provide new research directions and research strategies for the development of drugs from gut microbial metabolites. FUNDING STATEMENT: None.
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Affiliation(s)
- Yue Ma
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaolin Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jun Wang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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19
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Basu A, Singh R, Gupta S. Bacterial infections in cancer: A bilateral relationship. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2022; 14:e1771. [PMID: 34994112 DOI: 10.1002/wnan.1771] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 10/09/2021] [Accepted: 11/12/2021] [Indexed: 12/15/2022]
Abstract
Bacteria share a long commensal relationship with the human body. New findings, however, continue to unravel many complexities associated with this old alliance. In the past decades, the dysbiosis of human microbiome has been linked to tumorigenesis, and more recently to spontaneous colonization of existing tumors. The topic, however, remains open for debate as the claims for causative-prevailing dual characteristics of bacteria are mostly based on epidemiological evidence rather than robust mechanistic models. There are also no reviews linking the collective impact of bacteria in tumor microenvironments to the efficacy of cancer drugs, mechanisms of pathogen-initiated cancer and bacterial colonization, personalized nanomedicine, nanotechnology, and antimicrobial resistance. In this review, we provide a holistic overview of the bilateral relationship between cancer and bacteria covering all these aspects. Our collated evidence from the literature does not merely categorize bacteria as cancer causative or prevailing agents, but also critically highlights the gaps in the literature where more detailed studies may be required to reach such a conclusion. Arguments are made in favor of dual drug therapies that can simultaneously co-target bacteria and cancer cells to overcome drug resistance. Also discussed are the opportunities for leveraging the natural colonization and remission power of bacteria for cancer treatment. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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Affiliation(s)
- Abhirup Basu
- Department of Chemical Engineering, Indian Institute of Technology, Delhi, India
| | - Rohini Singh
- Department of Chemical Engineering, Indian Institute of Technology, Delhi, India
| | - Shalini Gupta
- Department of Chemical Engineering, Indian Institute of Technology, Delhi, India
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20
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Huang X, Li M, Hou S, Tian B. Role of the microbiome in systemic therapy for pancreatic ductal adenocarcinoma (Review). Int J Oncol 2021; 59:101. [PMID: 34738624 PMCID: PMC8577795 DOI: 10.3892/ijo.2021.5281] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/18/2021] [Indexed: 02/05/2023] Open
Abstract
A large body of evidence has revealed that the microbiome serves a role in all aspects of cancer, particularly cancer treatment. To date, studies investigating the relationship between the microbiome and systemic therapy for pancreatic ductal adenocarcinoma (PDAC) are lacking. PDAC is a high‑mortality malignancy (5‑year survival rate; <9% for all stages). Systemic therapy is one of the most important treatment choices for all patients; however, resistance or toxicity can affect its efficacy. Studies have supported the hypothesis that the microbiome is closely associated with the response to systemic therapy in PDAC, including the induction of drug resistance, or toxicity and therapy‑related changes in microbiota composition. The present review comprehensively summarized the role of the microbiome in systemic therapy for PDAC and the associated molecular mechanisms in an attempt to provide a novel direction for the improvement of treatment response and proposed potential directions for in‑depth research.
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Affiliation(s)
| | | | - Shengzhong Hou
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bole Tian
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
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21
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He Y, Liu QW, Liao HX, Xu WW. Microbiota in cancer chemoradiotherapy resistance. Clin Transl Med 2020; 11:e250. [PMID: 33463064 PMCID: PMC7774460 DOI: 10.1002/ctm2.250] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 11/10/2022] Open
Affiliation(s)
- Yan He
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Qin Wen Liu
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Hua Xin Liao
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Wen Wen Xu
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
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22
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Garajová I, Balsano R, Wang H, Leonardi F, Giovannetti E, Deng D, Peters GJ. The role of the microbiome in drug resistance in gastrointestinal cancers. Expert Rev Anticancer Ther 2020; 21:165-176. [PMID: 33115280 DOI: 10.1080/14737140.2021.1844007] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: The microbiota is recognized for its impact on both human health and disease. The human microbiota is made up of trillions of cells, including bacteria, viruses, and fungi. The largest population of microbes reside in the gut, prompting research for better understanding of the impact of gastrointestinal microbiota in different diseases. Evidence from numerous studies has pointed out the role of commensal microbes as key determinants of cancer pathogenesis. Moreover, gut microbiota may play an important role in chemoresistance; consequently, this knowledge might be important for novel strategies to improve anticancer treatment efficacy.Areas covered: We describe the role of microbiota in different gastrointestinal cancer types (esophageal, gastric, colorectal, hepatocellular and pancreatic-biliary tract cancers). Moreover, we analyzed the impact of the microbiota on resistance to anticancer therapies, and, lastly, we focused on possibilities of microbiota modulation to enhance anticancer therapy efficacy.Expert opinion: Increasing evidence shows that gut microbiota might influence resistance to anticancer treatment, including conventional chemotherapy, immunotherapy, radiotherapy, and surgery. Therefore, a better knowledge of gut microbiota and its interactions with anticancer drugs will enable us to develop novel anticancer treatment strategies and subsequently improve the cancer patients' outcome.
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Affiliation(s)
- Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Rita Balsano
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Heling Wang
- Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Amsterdam, The Netherlands
| | | | - Elisa Giovannetti
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.,Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienz, Pisa, Italy
| | - Dongmei Deng
- Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Amsterdam, The Netherlands
| | - Godefridus J Peters
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.,Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
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23
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Singh A, Nayak N, Rathi P, Verma D, Sharma R, Chaudhary A, Agarwal A, Tripathi YB, Garg N. Microbiome and host crosstalk: A new paradigm to cancer therapy. Semin Cancer Biol 2020; 70:71-84. [PMID: 32479952 DOI: 10.1016/j.semcancer.2020.05.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/19/2020] [Accepted: 05/22/2020] [Indexed: 12/17/2022]
Abstract
The commensal microbiome of humans has co-evolved for thousands of years. The microbiome regulates human health and is also linked to several diseases, including cancer. The advances in next-generation sequencing have significantly contributed to our understanding of the microbiome and its association with cancer and cancer therapy. Recent studies have highlighted a close relationship of the microbiome to the pharmacological effect of chemotherapy and immunotherapy. The chemo-drugs usually interfere with the host immune system and reduces the microbiome diversity inside the body, which in turn leads to decreased efficacy of these drugs. The human microbiome, specifically the gut microbiome, increases the potency of chemo-drugs through metabolism, enzymatic degradation, ecological differences, and immunomodulation. Recent research exploits the involvement of microbiome to shape the efficacy and decrease the toxicity of these chemo-drugs. In this review, we have highlighted the recent development in understanding the relationship of the human microbiome with cancer and also emphasize on various roles of the microbiome in the modulation of cancer therapy. Additionally, we also summarize the ongoing research focussed on the improved efficacy of chemotherapy and immunotherapy using the host microbiome.
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Affiliation(s)
- Ashutosh Singh
- School of Basic Sciences, Indian Institute of Technology Mandi, Mandi 175005, Himachal Pradesh, India
| | - Namyashree Nayak
- School of Basic Sciences, Indian Institute of Technology Mandi, Mandi 175005, Himachal Pradesh, India
| | - Preeti Rathi
- School of Basic Sciences, Indian Institute of Technology Mandi, Mandi 175005, Himachal Pradesh, India
| | - Deepanshu Verma
- School of Basic Sciences, Indian Institute of Technology Mandi, Mandi 175005, Himachal Pradesh, India
| | - Rohit Sharma
- Department of Rasashastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, BHU, Varanasi 221005, Uttar Pradesh, India
| | - Ashun Chaudhary
- Central University of Himachal Pradesh, Shahpur, Dist. Kangra, Himachal Pradesh 176206, India
| | - Alka Agarwal
- Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Sciences, BHU, Varanasi 221005, Uttar Pradesh, India
| | - Yamini Bhushan Tripathi
- Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Sciences, BHU, Varanasi 221005, Uttar Pradesh, India
| | - Neha Garg
- Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Sciences, BHU, Varanasi 221005, Uttar Pradesh, India.
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24
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Azevedo MM, Pina-Vaz C, Baltazar F. Microbes and Cancer: Friends or Faux? Int J Mol Sci 2020; 21:ijms21093115. [PMID: 32354115 PMCID: PMC7247677 DOI: 10.3390/ijms21093115] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 04/23/2020] [Accepted: 04/26/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer is one of the most aggressive and deadly diseases in the world, representing the second leading cause of death. It is a multifactorial disease, in which genetic alterations play a key role, but several environmental factors also contribute to its development and progression. Infections induced by certain viruses, bacteria, fungi and parasites constitute risk factors for cancer, being chronic infection associated to the development of certain types of cancer. On the other hand, susceptibility to infectious diseases is higher in cancer patients. The state of the host immune system plays a crucial role in the susceptibility to both infection and cancer. Importantly, immunosuppressive cancer treatments increase the risk of infection, by decreasing the host defenses. Furthermore, alterations in the host microbiota is also a key factor in the susceptibility to develop cancer. More recently, the identification of a tumor microbiota, in which bacteria establish a symbiotic relationship with cancer cells, opened a new area of research. There is evidence demonstrating that the interaction between bacteria and cancer cells can modulate the anticancer drug response and toxicity. The present review focuses on the interaction between microbes and cancer, specifically aiming to: (1) review the main infectious agents associated with development of cancer and the role of microbiota in cancer susceptibility; (2) highlight the higher vulnerability of cancer patients to acquire infectious diseases; (3) document the relationship between cancer cells and tissue microbiota; (4) describe the role of intratumoral bacteria in the response and toxicity to cancer therapy.
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Affiliation(s)
- Maria Manuel Azevedo
- Department of Microbiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- CINTESIS, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Agrupamento de Escolas D. Maria II, 4760-067 V.N. Famalicão, Portugal
- Correspondence: ; Tel.: +351-22-551-36
| | - Cidália Pina-Vaz
- Department of Microbiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- CINTESIS, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4835-258 Guimarães, Portugal
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25
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Lucafò M, Franzin M, Lagatolla C, Franca R, Bramuzzo M, Stocco G, Decorti G. Emerging Insights on the Interaction Between Anticancer and Immunosuppressant Drugs and Intestinal Microbiota in Pediatric Patients. Clin Transl Sci 2020; 13:238-259. [PMID: 31675176 PMCID: PMC7070880 DOI: 10.1111/cts.12722] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 10/23/2019] [Indexed: 02/06/2023] Open
Abstract
Diseases affecting the immune system, such as inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA), and acute lymphoblastic leukemia (ALL), are pathological conditions affecting the pediatric population and are often associated with alterations in the intestinal microbiota, such as a decrease in bacterial diversity. Growing evidence suggests that gut microbiota can interfere with chemotherapeutic and immunosuppressant drugs, used in the treatment of these diseases, reducing or facilitating drug efficacy. In particular, the effect of intestinal microflora through translocation, immunomodulation, metabolism, enzymatic degradation, and reduction of bacterial diversity seems to be one of the reasons of interindividual variability in the therapeutic response. Although the extent of the role of intestinal microflora in chemotherapy and immunosuppression remains still unresolved, current evidence on bacterial compositional shifts will be taken in consideration together with clinical response to drugs for a better and personalized therapy. This review is focused on the effect of the intestinal microbiota on the efficacy of pharmacological therapy of agents used to treat IBD, JIA, and ALL.
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Affiliation(s)
- Marianna Lucafò
- Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”TriesteItaly
| | - Martina Franzin
- PhD Course in Reproductive and Developmental SciencesUniversity of TriesteTriesteItaly
| | | | - Raffaella Franca
- Department of Medical, Surgical and Health SciencesUniversity of TriesteTriesteItaly
| | - Matteo Bramuzzo
- Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”TriesteItaly
| | - Gabriele Stocco
- Department of Life SciencesUniversity of TriesteTriesteItaly
| | - Giuliana Decorti
- Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”TriesteItaly
- Department of Medical, Surgical and Health SciencesUniversity of TriesteTriesteItaly
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Villéger R, Lopès A, Carrier G, Veziant J, Billard E, Barnich N, Gagnière J, Vazeille E, Bonnet M. Intestinal Microbiota: A Novel Target to Improve Anti-Tumor Treatment? Int J Mol Sci 2019; 20:ijms20184584. [PMID: 31533218 PMCID: PMC6770123 DOI: 10.3390/ijms20184584] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/12/2019] [Accepted: 09/13/2019] [Indexed: 12/18/2022] Open
Abstract
Recently, preclinical and clinical studies targeting several types of cancer strongly supported the key role of the gut microbiota in the modulation of host response to anti-tumoral therapies such as chemotherapy, immunotherapy, radiotherapy and even surgery. Intestinal microbiome has been shown to participate in the resistance to a wide range of anticancer treatments by direct interaction with the treatment or by indirectly stimulating host response through immunomodulation. Interestingly, these effects were described on colorectal cancer but also in other types of malignancies. In addition to their role in therapy efficacy, gut microbiota could also impact side effects induced by anticancer treatments. In the first part of this review, we summarized the role of the gut microbiome on the efficacy and side effects of various anticancer treatments and underlying mechanisms. In the second part, we described the new microbiota-targeting strategies, such as probiotics and prebiotics, antibiotics, fecal microbiota transplantation and physical activity, which could be effective adjuvant therapies developed in order to improve anticancer therapeutic efficiency.
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Affiliation(s)
- Romain Villéger
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH) UMR 1071 Inserm/Université Clermont Auvergne, USC-INRA 2018, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
| | - Amélie Lopès
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH) UMR 1071 Inserm/Université Clermont Auvergne, USC-INRA 2018, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
- Biologics Research, Sanofi R&D, 94400 Vitry-Sur-Seine, France.
| | - Guillaume Carrier
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH) UMR 1071 Inserm/Université Clermont Auvergne, USC-INRA 2018, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
- Surgical Oncology Department, Institut du Cancer de Montpellier (ICM), Univ Montpellier, 34298 Montpellier, France.
| | - Julie Veziant
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH) UMR 1071 Inserm/Université Clermont Auvergne, USC-INRA 2018, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
- Service de Chirurgie Digestive, CHU Clermont-Ferrand, Inserm, Université Clermont Auvergne, 63003 Clermont-Ferrand, France.
- 3iHP, CHU Clermont-Ferrand, Inserm, Université Clermont Auvergne, 63003 Clermont-Ferrand, France.
| | - Elisabeth Billard
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH) UMR 1071 Inserm/Université Clermont Auvergne, USC-INRA 2018, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
| | - Nicolas Barnich
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH) UMR 1071 Inserm/Université Clermont Auvergne, USC-INRA 2018, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
| | - Johan Gagnière
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH) UMR 1071 Inserm/Université Clermont Auvergne, USC-INRA 2018, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
- Service de Chirurgie Digestive, CHU Clermont-Ferrand, Inserm, Université Clermont Auvergne, 63003 Clermont-Ferrand, France.
- 3iHP, CHU Clermont-Ferrand, Inserm, Université Clermont Auvergne, 63003 Clermont-Ferrand, France.
| | - Emilie Vazeille
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH) UMR 1071 Inserm/Université Clermont Auvergne, USC-INRA 2018, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
- 3iHP, CHU Clermont-Ferrand, Inserm, Université Clermont Auvergne, 63003 Clermont-Ferrand, France.
- Service d'Hépato-gastro-entérologie, CHU Clermont-Ferrand, Inserm, Université Clermont Auvergne, 63003 Clermont-Ferrand, France.
| | - Mathilde Bonnet
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH) UMR 1071 Inserm/Université Clermont Auvergne, USC-INRA 2018, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
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Aarnoutse R, Ziemons J, Penders J, Rensen SS, de Vos-Geelen J, Smidt ML. The Clinical Link between Human Intestinal Microbiota and Systemic Cancer Therapy. Int J Mol Sci 2019; 20:E4145. [PMID: 31450659 PMCID: PMC6747354 DOI: 10.3390/ijms20174145] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 08/21/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023] Open
Abstract
Clinical interest in the human intestinal microbiota has increased considerably. However, an overview of clinical studies investigating the link between the human intestinal microbiota and systemic cancer therapy is lacking. This systematic review summarizes all clinical studies describing the association between baseline intestinal microbiota and systemic cancer therapy outcome as well as therapy-related changes in intestinal microbiota composition. A systematic literature search was performed and provided 23 articles. There were strong indications for a close association between the intestinal microbiota and outcome of immunotherapy. Furthermore, the development of chemotherapy-induced infectious complications seemed to be associated with the baseline microbiota profile. Both chemotherapy and immunotherapy induced drastic changes in gut microbiota composition with possible consequences for treatment efficacy. Evidence in the field of hormonal therapy was very limited. Large heterogeneity concerning study design, study population, and methods used for analysis limited comparability and generalization of results. For the future, longitudinal studies investigating the predictive ability of baseline intestinal microbiota concerning treatment outcome and complications as well as the potential use of microbiota-modulating strategies in cancer patients are required. More knowledge in this field is likely to be of clinical benefit since modulation of the microbiota might support cancer therapy in the future.
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Affiliation(s)
- Romy Aarnoutse
- GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands.
- Department of Surgery, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands.
| | - Janine Ziemons
- GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands
| | - John Penders
- Department of Medical Microbiology, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands
- NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
| | - Sander S Rensen
- Department of Surgery, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands
- NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
| | - Judith de Vos-Geelen
- GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
- Department of Internal Medicine, Division of Medical Oncology, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands
| | - Marjolein L Smidt
- GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands
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Hekmatshoar Y, Rahbar Saadat Y, Hosseiniyan Khatibi SM, Ozkan T, Zununi Vahed F, Nariman-Saleh-Fam Z, Pourghassem Gargari B, Sunguroglu A, Zununi Vahed S. The impact of tumor and gut microbiotas on cancer therapy: Beneficial or detrimental? Life Sci 2019; 233:116680. [PMID: 31344431 DOI: 10.1016/j.lfs.2019.116680] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/15/2019] [Accepted: 07/21/2019] [Indexed: 12/18/2022]
Abstract
Cancer is a globally challenging health problem threatening mankind. Despite therapeutic advances in dealing with this malignancy, heterogeneous response and resistance to chemotherapeutic agents remain the hallmarks of cancer therapy. On the other hand, the involvement of the microbiota in affecting human health is well defined. An ever-growing body of evidence implicates the potential link between the microbiome and the efficacy of cancer therapies. Gut microbiota can modulate the metabolism of drugs in a number of ways. The presence of bacteria within the tumor environment can also impact the responses to cancer therapies; changing the chemical structure of chemotherapeutic drugs, affecting their activity, and local concentration. However, the underlying mechanisms by which gut and tumor microbial communities affect the response to cancer therapy are poorly understood and deciphering these mechanisms is of paramount importance. This review provides an overview of how gut and tumor microbiota might affect the efficacy of chemotherapy, radiotherapy, and immunotherapy and alleviate the adverse side effects of these therapies for the development of personalized and effective anticancer therapy.
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Affiliation(s)
- Yalda Hekmatshoar
- Department of Medical Biology, School of Medicine, Ankara University, Ankara, Turkey
| | - Yalda Rahbar Saadat
- Nutrition Research Center, Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyed Mahdi Hosseiniyan Khatibi
- International Rice Research Institute (IRRI), Los Banos, Philippines; Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tulin Ozkan
- Department of Medical Biology, School of Medicine, Ankara University, Ankara, Turkey
| | | | - Ziba Nariman-Saleh-Fam
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahram Pourghassem Gargari
- Nutrition Research Center, Department of Biochemistry and Diet Therapy, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Asuman Sunguroglu
- Department of Medical Biology, School of Medicine, Ankara University, Ankara, Turkey
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Chamseddine AN, Ducreux M, Armand JP, Paoletti X, Satar T, Paci A, Mir O. Intestinal bacterial β-glucuronidase as a possible predictive biomarker of irinotecan-induced diarrhea severity. Pharmacol Ther 2019; 199:1-15. [DOI: 10.1016/j.pharmthera.2019.03.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Villéger R, Lopès A, Veziant J, Gagnière J, Barnich N, Billard E, Boucher D, Bonnet M. Microbial markers in colorectal cancer detection and/or prognosis. World J Gastroenterol 2018; 24:2327-2347. [PMID: 29904241 PMCID: PMC6000297 DOI: 10.3748/wjg.v24.i22.2327] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 05/03/2018] [Accepted: 05/18/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer worldwide. CRC is still associated with a poor prognosis among patients with advanced disease. On the contrary, due to its slow progression from detectable precancerous lesions, the prognosis for patients with early stages of CRC is encouraging. While most robust methods are invasive and costly, actual patient-friendly screening methods for CRC suffer of lack of sensitivity and specificity. Therefore, the development of sensitive, non-invasive and cost-effective methods for CRC detection and prognosis are necessary for increasing the chances of a cure. Beyond its beneficial functions for the host, increasing evidence suggests that the intestinal microbiota is a key factor associated with carcinogenesis. Many clinical studies have reported a disruption in the gut microbiota balance and an alteration in the faecal metabolome of CRC patients, suggesting the potential use of a microbial-based test as a non-invasive diagnostic and/or prognostic tool for CRC screening. This review aims to discuss the microbial signatures associated with CRC known to date, including dysbiosis and faecal metabolome alterations, and the potential use of microbial variation markers for non-invasive early diagnosis and/or prognostic assessment of CRC and advanced adenomas. We will finally discuss the possible use of these markers as predicators for treatment response and their limitations.
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Affiliation(s)
- Romain Villéger
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
| | - Amélie Lopès
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Research Biologics, Sanofi R&D, Vitry-Sur-Seine 94400, France
| | - Julie Veziant
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Chirurgie digestive, Centre Hospitalier Universitaire, Clermont-Ferrand 63000, France
| | - Johan Gagnière
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Chirurgie digestive, Centre Hospitalier Universitaire, Clermont-Ferrand 63000, France
| | - Nicolas Barnich
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Université Clermont Auvergne, Institut Universitaire de Technologie de Clermont-Ferrand, Clermont-Ferrand 63000, France
| | - Elisabeth Billard
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Université Clermont Auvergne, Institut Universitaire de Technologie de Clermont-Ferrand, Clermont-Ferrand 63000, France
| | - Delphine Boucher
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Université Clermont Auvergne, Institut Universitaire de Technologie de Clermont-Ferrand, Clermont-Ferrand 63000, France
| | - Mathilde Bonnet
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Université Clermont Auvergne, Institut Universitaire de Technologie de Clermont-Ferrand, Clermont-Ferrand 63000, France
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31
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Geller LT, Straussman R. Intratumoral bacteria may elicit chemoresistance by metabolizing anticancer agents. Mol Cell Oncol 2017; 5:e1405139. [PMID: 29404397 DOI: 10.1080/23723556.2017.1405139] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 11/07/2017] [Accepted: 11/07/2017] [Indexed: 12/19/2022]
Abstract
We recently reported that bacteria can be found within pancreatic ductal adenocarcinoma (PDAC) tumors. Some of these bacteria can metabolize and thereby inactivate the nucleoside analog gemcitabine. We demonstrated that the long isoform of the bacterial enzyme cytidine deaminase (CDD) mediates the metabolism of gemcitabine. The clinical effect of overcoming this potential mechanism of drug resistance has yet to be studied.
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Affiliation(s)
- Leore T Geller
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ravid Straussman
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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Li W, Yue H. Thymidine phosphorylase: A potential new target for treating cardiovascular disease. Trends Cardiovasc Med 2017; 28:157-171. [PMID: 29108898 DOI: 10.1016/j.tcm.2017.10.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 10/03/2017] [Accepted: 10/17/2017] [Indexed: 12/21/2022]
Abstract
We recently found that thymidine phosphorylase (TYMP), also known as platelet-derived endothelial cell growth factor, plays an important role in platelet activation in vitro and thrombosis in vivo by participating in multiple signaling pathways. Platelets are a major source of TYMP. Since platelet-mediated clot formation is a key event in several fatal diseases, such as myocardial infarction, stroke and pulmonary embolism, understanding TYMP in depth may lead to uncovering novel mechanisms in the development of cardiovascular diseases. Targeting TYMP may become a novel therapeutic for cardiovascular disorders. In this review article, we summarize the discovery of TYMP and the potential molecular mechanisms of TYMP involved in the development of various diseases, especially cardiovascular diseases. We also offer insights regarding future studies exploring the role of TYMP in the development of cardiovascular disease as well as in therapy.
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Affiliation(s)
- Wei Li
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall, University, Huntington, WV; Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, WV.
| | - Hong Yue
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall, University, Huntington, WV
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Liu D, Hu Y, Guo Y, Zhu Z, Lu B, Wang X, Huang Y. Mycoplasma-associated multidrug resistance of hepatocarcinoma cells requires the interaction of P37 and Annexin A2. PLoS One 2017; 12:e0184578. [PMID: 28976984 PMCID: PMC5627893 DOI: 10.1371/journal.pone.0184578] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 08/26/2017] [Indexed: 12/15/2022] Open
Abstract
Mycoplasma infection has been reported to be associated with cancer migration, invasion, epithelial-mesenchymal transition as well as the resistance to nucleoside analogues chemotherapeutic drugs. In this study, we found that the sensitivity of hepatocarcinoma cells to Cisplatin, Gemcitabine and Mitoxantrone was increased by mycoplasma elimination. Similar to the effect of anti-mycoplasma agent, interrupting the interaction between Mycoplasma hyorhinis membrane protein P37 and Annexin A2 of host cells using the N-terminal of ANXA2 polypeptide enhanced the sensitivity of HCC97L cells to Gemcitabine and Mitoxantrone. Meanwhile, we did not observe any changes in expression or distribution of multidrug resistance associated transporters, ATP-Binding Cassette protein B1, C1 and G2, on the removal of mycoplasma. These results suggest that mycoplasma induces a resistance to multiple drugs in hepatocarcinoma cells which required the interaction of P37 and Annexin A2. The pathway downstream this interaction needs to be explored.
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Affiliation(s)
- Danyang Liu
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yang Hu
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ying Guo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China
| | - Zhu Zhu
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Bingzheng Lu
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xuelan Wang
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- * E-mail: (YH); (XW)
| | - Yijun Huang
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- * E-mail: (YH); (XW)
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Abstract
Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidence from human, animal and in vitro studies that gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies. The gut microbiota modulate these agents through key mechanisms, structured as the 'TIMER' mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation. The gut microbiota can now, therefore, be targeted to improve efficacy and reduce the toxicity of current chemotherapy agents. In this Review, we outline the implications of pharmacomicrobiomics in cancer therapeutics and define how the microbiota might be modified in clinical practice to improve efficacy and reduce the toxic burden of these compounds.
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Vande Voorde J, Vervaeke P, Liekens S, Balzarini J. Mycoplasma hyorhinis-encoded cytidine deaminase efficiently inactivates cytosine-based anticancer drugs. FEBS Open Bio 2015; 5:634-9. [PMID: 26322268 PMCID: PMC4541722 DOI: 10.1016/j.fob.2015.07.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 07/24/2015] [Accepted: 07/30/2015] [Indexed: 11/25/2022] Open
Abstract
Mycoplasmas may colonize tumor tissue in patients. Mycoplasma-encoded cytidine deaminase deaminates cytosine-based anticancer drugs. The activity of gemcitabine is compromised in mycoplasma-infected tumor cells. Gemcitabine activity can be restored by nucleosides or a PNP inhibitor. Mycoplasmas may colonize tumor tissue in patients. The cytostatic activity of gemcitabine was dramatically decreased in Mycoplasma hyorhinis-infected tumor cell cultures compared with non-infected tumor cell cultures. This mycoplasma-driven drug deamination could be prevented by exogenous administration of the cytidine deaminase (CDA) inhibitor tetrahydrouridine, but also by the natural nucleosides or by a purine nucleoside phosphorylase inhibitor. The M. hyorhinis-encoded CDAHyor gene was cloned, expressed as a recombinant protein and purified. CDAHyor was found to be more catalytically active than its human equivalent and efficiently deaminates (inactivates) cytosine-based anticancer drugs. CDAHyor expression at the tumor site may result in selective drug inactivation and suboptimal therapeutic efficiency.
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Key Words
- (d)Ado, (2′-deoxy)adenosine
- (d)Guo, (2′-deoxy)guanosine
- (d)Ino, (2′-deoxy)inosine
- (d)Urd, (2′-deoxy)uridine
- 3TC, 2′,3′-dideoxy-3′-thiacytidine
- CDA, cytidine deaminase
- Cancer
- Cytidine deaminase
- Gemcitabine
- Imm-H, Immucillin-H
- Mycoplasma
- NA, nucleoside analogue
- Nucleoside analogue
- PNP, purine nucleoside phosphorylase
- Purine nucleoside phosphorylase
- ara-Cyd, cytosine arabinoside
- dFdC, gemcitabine
- dFdU, 2′,2′-difluoro-2′-deoxyuridine
- dThd, thymidine
- ddC, 2′,3′-dideoxycytidine
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Affiliation(s)
| | | | | | - Jan Balzarini
- Corresponding author. Tel.: +32 16 337367; fax: +32 16 337340.
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Vande Voorde J, Liekens S, Gago F, Balzarini J. The pyrimidine nucleoside phosphorylase of Mycoplasma hyorhinis and how it may affect nucleoside-based therapy. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2015; 33:394-402. [PMID: 24940697 DOI: 10.1080/15257770.2013.851394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Mycoplasmas are opportunistic parasites and some species are suggested to preferentially colonize tumor tissue in cancer patients. We could demonstrate that the annotated thymidine phosphorylase (TP) gene in the genome of Mycoplasma hyorhinis encodes a pyrimidine nucleoside phosphorylase (PyNPHyor) that not only efficiently catalyzes thymidine but also uridine phosphorolysis. The kinetic characteristics of PyNPHyor-catalyzed nucleoside and nucleoside analogue (NA) phosphorolysis were determined. We demonstrated that the expression of such an enzyme in mycoplasma-infected cell cultures dramatically alters the activity of various anticancer/antiviral NAs such as 5-halogenated pyrimidine nucleosides, including 5-trifluorothymidine (TFT). Due to their close association with human cancers, the presence of mycoplasmas may markedly influence the therapeutic efficiency of nucleoside-based drugs.
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Affiliation(s)
- J Vande Voorde
- a Rega Institute for Medical Research , KU Leuven , Leuven , Belgium
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Wang L, Schmidl SR, Stülke J. Mycoplasma pneumoniae thymidine phosphorylase. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2015; 33:296-304. [PMID: 24940683 DOI: 10.1080/15257770.2013.853783] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Mycoplasma pneumoniae (Mpn) is a human pathogen causing acute respiratory diseases and accounts for approximately 30% cases of community-acquired pneumonia. Co-infection with Mycoplasmas compromises the efficacy of anticancer and antiviral nucleoside analog-based drugs due to the presence of Mycoplasma thymidine phosphorylase (TP). In this study, a TP-deficient strain of Mpn was generated in order to study the effect of Mpn TP in the metabolism of nucleoside analogs. Deficiency in TP activity led to increased uptake and incorporation of radiolabeled deoxyuridine and uracil but thymidine uptake was not affected. The activities of enzymes in the salvage of thymidine and deoxyuridine, e.g., thymidine kinase and uracil phosphoribosyltransferase were upregulated in the TP-deficient mutant, which may explain the increased uptake of deoxyuridine and uracil. Thirty FDA-approved anticancer and antiviral nucleoside and nucleobase analogs were used to screen their inhibitory activity toward the TP mutant and the wild type strain. Seven analogs were found to inhibit strongly the growth of both wild type and TP mutant. Differences in the inhibitory effect of several purine analogs between the two strains were observed. Further study is needed in order to understand the mechanism of inhibition caused by these analogs. Our results indicated that TP is not an essential gene for Mpn survival and TP deficiency affects other enzymes in Mpn nucleotide metabolism, and suggested that Mycoplasma nucleotide biosynthesis pathway enzymes are potential targets for future development of antibiotics.
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Affiliation(s)
- Liya Wang
- a Department of Anatomy, Physiology and Biochemistry , Swedish University of Agricultural Sciences, The Biomedical Center , Uppsala , Sweden
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Vande Voorde J, Sabuncuoğlu S, Noppen S, Hofer A, Ranjbarian F, Fieuws S, Balzarini J, Liekens S. Nucleoside-catabolizing enzymes in mycoplasma-infected tumor cell cultures compromise the cytostatic activity of the anticancer drug gemcitabine. J Biol Chem 2014; 289:13054-65. [PMID: 24668817 DOI: 10.1074/jbc.m114.558924] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The intracellular metabolism and cytostatic activity of the anticancer drug gemcitabine (2',2'-difluoro-2'-deoxycytidine; dFdC) was severely compromised in Mycoplasma hyorhinis-infected tumor cell cultures. Pronounced deamination of dFdC to its less cytostatic metabolite 2',2'-difluoro-2'-deoxyuridine was observed, both in cell extracts and spent culture medium (i.e. tumor cell-free but mycoplasma-containing) of mycoplasma-infected tumor cells. This indicates that the decreased antiproliferative activity of dFdC in such cells is attributed to a mycoplasma cytidine deaminase causing rapid drug catabolism. Indeed, the cytostatic activity of gemcitabine could be restored by the co-administration of tetrahydrouridine (a potent cytidine deaminase inhibitor). Additionally, mycoplasma-derived pyrimidine nucleoside phosphorylase (PyNP) activity indirectly potentiated deamination of dFdC: the natural pyrimidine nucleosides uridine, 2'-deoxyuridine and thymidine inhibited mycoplasma-associated dFdC deamination but were efficiently catabolized (removed) by mycoplasma PyNP. The markedly lower anabolism and related cytostatic activity of dFdC in mycoplasma-infected tumor cells was therefore also (partially) restored by a specific TP/PyNP inhibitor (TPI), or by exogenous thymidine. Consequently, no effect on the cytostatic activity of dFdC was observed in tumor cell cultures infected with a PyNP-deficient Mycoplasma pneumoniae strain. Because it has been reported that some commensal mycoplasma species (including M. hyorhinis) preferentially colonize tumor tissue in cancer patients, our findings suggest that the presence of mycoplasmas in the tumor microenvironment could be a limiting factor for the anticancer efficiency of dFdC-based chemotherapy. Accordingly, a significantly decreased antitumor effect of dFdC was observed in mice bearing M. hyorhinis-infected murine mammary FM3A tumors compared with uninfected tumors.
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Affiliation(s)
- Johan Vande Voorde
- From the Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, blok x-bus 1030, B-3000 Leuven, Belgium
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Vande Voorde J, Liekens S, Balzarini J. Mycoplasma hyorhinis-encoded purine nucleoside phosphorylase: kinetic properties and its effect on the cytostatic potential of purine-based anticancer drugs. Mol Pharmacol 2013; 84:865-75. [PMID: 24068428 DOI: 10.1124/mol.113.088625] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
A mycoplasma-encoded purine nucleoside phosphorylase (designated PNPHyor) has been cloned and characterized for the first time. Efficient phosphorolysis of natural 6-oxopurine and 6-aminopurine nucleosides was observed, with adenosine the preferred natural substrate (Km = 61 µM). Several cytostatic purine nucleoside analogs proved to be susceptible to PNPHyor-mediated phosphorolysis, and a markedly decreased or increased cytostatic activity was observed in Mycoplasma hyorhinis-infected human breast carcinoma MCF-7 cell cultures (MCF-7.Hyor), depending on the properties of the released purine base. We demonstrated an ∼10-fold loss of cytostatic activity of cladribine in MCF-7.Hyor cells and observed a rapid and complete phosphorolysis of this drug when it was exposed to the supernatant of mycoplasma-infected cells. This conversion (inactivation) could be prevented by a specific PNP inhibitor. These findings correlated well with the high efficiency of PNPHyor-catalyzed phosphorolysis of cladribine to its less toxic base 2-chloroadenine (Km = 80 µM). In contrast, the cytostatic activity of nucleoside analogs carrying a highly toxic purine base and being a substrate for PNPHyor, but not human PNP, was substantially increased in MCF-7.Hyor cells (∼130-fold for fludarabine and ∼45-fold for 6-methylpurine-2'-deoxyriboside). Elimination of the mycoplasma from the tumor cell cultures or selective inhibition of PNPHyor by a PNP inhibitor restored the cytostatic activity of the purine-based nucleoside drugs. Since several studies suggest a high and preferential colonization or association of tumor tissue in cancer patients with different prokaryotes (including mycoplasmas), the data presented here may be of relevance for the optimization of purine nucleoside-based anticancer drug treatment.
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Romorini L, Riva DA, Blüguermann C, Videla Richardson GA, Scassa ME, Sevlever GE, Miriuka SG. Effect of antibiotics against Mycoplasma sp. on human embryonic stem cells undifferentiated status, pluripotency, cell viability and growth. PLoS One 2013; 8:e70267. [PMID: 23936178 PMCID: PMC3728093 DOI: 10.1371/journal.pone.0070267] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 06/17/2013] [Indexed: 12/31/2022] Open
Abstract
Human embryonic stem cells (hESCs) are self-renewing pluripotent cells that can differentiate into specialized cells and hold great promise as models for human development and disease studies, cell-replacement therapies, drug discovery and in vitro cytotoxicity tests. The culture and differentiation of these cells are both complex and expensive, so it is essential to extreme aseptic conditions. hESCs are susceptible to Mycoplasma sp. infection, which is hard to detect and alters stem cell-associated properties. The purpose of this work was to evaluate the efficacy and cytotoxic effect of PlasmocinTM and ciprofloxacin (specific antibiotics used for Mycoplasma sp. eradication) on hESCs. Mycoplasma sp. infected HUES-5 884 (H5 884, stable hESCs H5-brachyury promoter-GFP line) cells were effectively cured with a 14 days PlasmocinTM 25 µg/ml treatment (curative treatment) while maintaining stemness characteristic features. Furthermore, cured H5 884 cells exhibit the same karyotype as the parental H5 line and expressed GFP, through up-regulation of brachyury promoter, at day 4 of differentiation onset. Moreover, H5 cells treated with ciprofloxacin 10 µg/ml for 14 days (mimic of curative treatment) and H5 and WA09 (H9) hESCs treated with PlasmocinTM 5 µg/ml (prophylactic treatment) for 5 passages retained hESCs features, as judged by the expression of stemness-related genes (TRA1-60, TRA1-81, SSEA-4, Oct-4, Nanog) at mRNA and protein levels. In addition, the presence of specific markers of the three germ layers (brachyury, Nkx2.5 and cTnT: mesoderm; AFP: endoderm; nestin and Pax-6: ectoderm) was verified in in vitro differentiated antibiotic-treated hESCs. In conclusion, we found that PlasmocinTM and ciprofloxacin do not affect hESCs stemness and pluripotency nor cell viability. However, curative treatments slightly diminished cell growth rate. This cytotoxic effect was reversible as cells regained normal growth rate upon antibiotic withdrawal.
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Affiliation(s)
- Leonardo Romorini
- Laboratorio de Biología del Desarrollo Celular, Laboratorios de Investigación Aplicada en Nuerociencias - Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Escobar, Buenos Aires, Argentina
| | - Diego Ariel Riva
- Laboratorio de Biología del Desarrollo Celular, Laboratorios de Investigación Aplicada en Nuerociencias - Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Escobar, Buenos Aires, Argentina
| | - Carolina Blüguermann
- Laboratorio de Biología del Desarrollo Celular, Laboratorios de Investigación Aplicada en Nuerociencias - Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Escobar, Buenos Aires, Argentina
| | - Guillermo Agustin Videla Richardson
- Laboratorio de Biología del Desarrollo Celular, Laboratorios de Investigación Aplicada en Nuerociencias - Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Escobar, Buenos Aires, Argentina
| | - Maria Elida Scassa
- Laboratorio de Biología del Desarrollo Celular, Laboratorios de Investigación Aplicada en Nuerociencias - Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Escobar, Buenos Aires, Argentina
| | - Gustavo Emilio Sevlever
- Laboratorio de Biología del Desarrollo Celular, Laboratorios de Investigación Aplicada en Nuerociencias - Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Escobar, Buenos Aires, Argentina
| | - Santiago Gabriel Miriuka
- Laboratorio de Biología del Desarrollo Celular, Laboratorios de Investigación Aplicada en Nuerociencias - Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Escobar, Buenos Aires, Argentina
- * E-mail:
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Singh VP, Tiwari K, Mishra M. Synthesis, spectral and thermal studies of some polymeric mixed ligand uracil–hydrazide complexes with transition metal ions. Des Monomers Polym 2012. [DOI: 10.1080/15685551.2012.747164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Affiliation(s)
- Vinod P. Singh
- a Department of Chemistry , Banaras Hindu University , Varanasi , 221005 , India
| | - Karishma Tiwari
- a Department of Chemistry , Banaras Hindu University , Varanasi , 221005 , India
| | - Monika Mishra
- a Department of Chemistry , Banaras Hindu University , Varanasi , 221005 , India
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Characterization of pyrimidine nucleoside phosphorylase of Mycoplasma hyorhinis: implications for the clinical efficacy of nucleoside analogues. Biochem J 2012; 445:113-23. [PMID: 22475552 DOI: 10.1042/bj20112225] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
In the present paper we demonstrate that the cytostatic and antiviral activity of pyrimidine nucleoside analogues is markedly decreased by a Mycoplasma hyorhinis infection and show that the phosphorolytic activity of the mycoplasmas is responsible for this. Since mycoplasmas are (i) an important cause of secondary infections in immunocompromised (e.g. HIV infected) patients and (ii) known to preferentially colonize tumour tissue in cancer patients, catabolic mycoplasma enzymes may compromise efficient chemotherapy of virus infections and cancer. In the genome of M. hyorhinis, a TP (thymidine phosphorylase) gene has been annotated. This gene was cloned, expressed in Escherichia coli and kinetically characterized. Whereas the mycoplasma TP efficiently catalyses the phosphorolysis of thymidine (Km=473 μM) and deoxyuridine (Km=578 μM), it prefers uridine (Km=92 μM) as a substrate. Our kinetic data and sequence analysis revealed that the annotated M. hyorhinis TP belongs to the NP (nucleoside phosphorylase)-II class PyNPs (pyrimidine NPs), and is distinct from the NP-II class TP and NP-I class UPs (uridine phosphorylases). M. hyorhinis PyNP also markedly differs from TP and UP in its substrate specificity towards therapeutic nucleoside analogues and susceptibility to clinically relevant drugs. Several kinetic properties of mycoplasma PyNP were explained by in silico analyses.
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Rivero CW, Britos CN, Lozano ME, Sinisterra JV, Trelles JA. Green biosynthesis of floxuridine by immobilized microorganisms. FEMS Microbiol Lett 2012; 331:31-6. [DOI: 10.1111/j.1574-6968.2012.02547.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Revised: 03/08/2012] [Accepted: 03/12/2012] [Indexed: 01/01/2023] Open
Affiliation(s)
- Cintia W. Rivero
- Laboratorio de Investigaciones en Biotecnología Sustentable (LIBioS); Universidad Nacional de Quilmes; Bernal; Argentina
| | - Claudia N. Britos
- Laboratorio de Investigaciones en Biotecnología Sustentable (LIBioS); Universidad Nacional de Quilmes; Bernal; Argentina
| | - Mario E. Lozano
- Laboratorio de Investigaciones en Biotecnología Sustentable (LIBioS); Universidad Nacional de Quilmes; Bernal; Argentina
| | - Jose V. Sinisterra
- Servicio de Biotransformaciones Industriales (SBI); Parque Científico de Madrid, C/Santiago Grisolía; Madrid; España
| | - Jorge A. Trelles
- Laboratorio de Investigaciones en Biotecnología Sustentable (LIBioS); Universidad Nacional de Quilmes; Bernal; Argentina
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Inhibition of pyrimidine and purine nucleoside phosphorylases by a 3,5-dichlorobenzoyl-substituted 2-deoxy-D-ribose-1-phosphate derivative. Biochem Pharmacol 2012; 83:1358-63. [PMID: 22366108 DOI: 10.1016/j.bcp.2012.02.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Revised: 02/08/2012] [Accepted: 02/09/2012] [Indexed: 11/23/2022]
Abstract
The 3,5-dichlorobenzoyl-substituted 2-deoxy-D-ribose-1-phosphate derivative, designated Cf2891, was found to inhibit a variety of pyrimidine and purine nucleoside phosphorylases (NPs) with preference for uridine- and inosine-hydrolyzing enzymes [uridine phosphorylase (UP; EC 2.4.2.3), pyrimidine nucleoside phosphorylase (PyNP; EC 2.4.2.2) and purine nucleoside phosphorylase (PNP; EC 2.4.2.1)]. Kinetic analyses revealed that Cf2891 competes with inorganic phosphate (P(i)) for binding to the NPs and, depending on the nature of the enzyme, acts as a competitive or non-competitive inhibitor with regard to the nucleoside binding site. Also, the compound prevents breakdown of pyrimidine analogues used in the treatment of viral infections and cancer. Since NPs are abundantly present in tumor tissue and may be overexpressed due to secondary bacterial infections in immunocompromised patients suffering viral infections, Cf2891 may serve as a lead molecule for the development of inhibitors to be used in nucleoside-based combination therapy.
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McGuigan C, Murziani P, Slusarczyk M, Gonczy B, Vande Voorde J, Liekens S, Balzarini J. Phosphoramidate ProTides of the Anticancer Agent FUDR Successfully Deliver the Preformed Bioactive Monophosphate in Cells and Confer Advantage over the Parent Nucleoside. J Med Chem 2011; 54:7247-58. [DOI: 10.1021/jm200815w] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Christopher McGuigan
- Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, U.K
| | - Paola Murziani
- Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, U.K
| | - Magdalena Slusarczyk
- Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, U.K
| | - Blanka Gonczy
- Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, U.K
| | - Johan Vande Voorde
- Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium
| | - Sandra Liekens
- Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium
| | - Jan Balzarini
- Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium
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Vande Voorde J, Liekens S, McGuigan C, Murziani PG, Slusarczyk M, Balzarini J. The cytostatic activity of NUC-3073, a phosphoramidate prodrug of 5-fluoro-2′-deoxyuridine, is independent of activation by thymidine kinase and insensitive to degradation by phosphorolytic enzymes. Biochem Pharmacol 2011; 82:441-52. [DOI: 10.1016/j.bcp.2011.05.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Revised: 05/20/2011] [Accepted: 05/23/2011] [Indexed: 11/29/2022]
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Molla Kazemiha V, Azari S, Amanzadeh A, Bonakdar S, Shojaei Moghadam M, Habibi Anbouhi M, Maleki S, Ahmadi N, Mousavi T, Shokrgozar MA. Efficiency of Plasmocin™ on various mammalian cell lines infected by mollicutes in comparison with commonly used antibiotics in cell culture: a local experience. Cytotechnology 2011; 63:609-20. [PMID: 21866311 DOI: 10.1007/s10616-011-9378-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Accepted: 07/19/2011] [Indexed: 01/19/2023] Open
Abstract
Mycoplasma contamination is a deleterious event for cell culture laboratories. Plasmocin™ is used to prevent and eradicate mycoplasma infections from cell. In this study, 80 different mammalian cell lines from various sources; human, monkey, mice, hamster and rat were used to study and evaluate plasmocin™ efficiency and compare it to commonly used antibiotics such as BM-cyclin, ciprofloxacin and mycoplasma removal agent (MRA). It was shown that mycoplasma infections were eradicated by plasmocin™, BM-cyclin, ciprofloxacin and MRA in 65%, 66.25%, 20%, and 31.25%, respectively, of infected cell cultures. However, re-infection with mycoplasmas after the period of 4 months occurred in 10-80% of the studied cell lines. Cell cytotoxicity and culture death was observed in 25, 17.5 and 10% of the treated cells, for plasmocin™, BM-cyclin and MRA, respectively. In this study, Plasmocin™ showed strong ability to eradicate mollicutes from our cell lines with minimal percentage of regrowth. However, due to its high cell cytotoxicity it should be used with caution especially when dealing with expensive or hard-to-obtain cell lines. Amongst the antibiotics tested, BM-cyclin was shown to remove mycoplasma with the highest efficiency.
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Shibata T, Kawasaki SY, Fujita JY, Kabashima T, Kai M. A novel and specific fluorescence reaction for uracil. Anal Chim Acta 2010; 674:234-8. [PMID: 20678635 DOI: 10.1016/j.aca.2010.06.028] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2010] [Revised: 06/16/2010] [Accepted: 06/22/2010] [Indexed: 11/29/2022]
Abstract
Facile and specific methods to quantify a nucleobase in biological samples are of great importance for diagnosing disorders in nucleic acid metabolism. In the present study, a novel fluorogenic reaction specific for uracil has been developed. The reaction was carried out in an alkaline medium containing benzamidoxime and K(3)[Fe(CN)(6)] which were heated for 2.0 min. Under the optimum reaction conditions, strong fluorescence was produced only from uracil, not from other many biogenic compounds tested such as cytosine, thymine, adenine, guanine, nucleobases, nucleosides, nucleotides, amino acids, saccharides, creatine, creatinine and urea. The sensitivity of this method was compared with a known fluorogenic reaction using phenacylbromide which does not react with uracil but reacts with cytosine, adenine and their analogues. The proposed uracil-specific reaction showed approximately 400-fold higher sensitivity than the phenacylbromide reaction. The lower detection limit of uracil by the present method was 100 pmol mL(-1), and a good linearity of the calibration curve was obtained up to 100 nmol mL(-1) uracil. Due to its high sensitivity and specificity, the quantitative determination of uracil was possible by the proposed fluorimetric method.
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Affiliation(s)
- Takayuki Shibata
- Faculty of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-Machi, Nagasaki 852-8521, Japan
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Qu B, Wang W, Tan Z, Li D, Wan J, Sun J, Cheng K, Luo H. Diethyl (6-amino-9H-purin-9-yl) methylphosphonate induces apoptosis and cell cycle arrest in hepatocellular carcinoma BEL-7402 cells: Role of reactive oxygen species. Free Radic Res 2010; 44:881-90. [PMID: 20528564 DOI: 10.3109/10715762.2010.487868] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The primary purpose of this work was to study the mechanism of the anti-proliferation activity of compound diethyl (6-amino-9H-purin-9-yl) methylphosphonate (DaMP), a novel acyclic nucleoside phosphonate. Using cell survival MTT assay, flow cytometry analysis, DNA laddering, DCF fluorescence detection and caspases assays, this study investigated the effects of this compound on cell apoptosis, cell cycle regulation and reactive oxygen species in human hepatocarcinoma BEL-7402 cell lines. Exposure to DaMP at 80 microM for 24 h, BEL-7402 cells displayed a marked retardation of S-phase progression, leading to a severe perturbation of normal cell cycle. In addition, DaMP also significantly inhibited cell proliferation by inducing apoptosis, disrupting DNA synthesis and increasing the activities of caspase-3 and -9, while the antioxidants could significantly inhibit these effects. This study was the first to demonstrate that DaMP could induce apoptosis and cell cycle arrest by producing reactive oxygen species and activating caspase-3 and -9.
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Affiliation(s)
- Bin Qu
- College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, 266042, PR China.
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Bronckaers A, Gago F, Balzarini J, Liekens S. The dual role of thymidine phosphorylase in cancer development and chemotherapy. Med Res Rev 2009; 29:903-53. [PMID: 19434693 PMCID: PMC7168469 DOI: 10.1002/med.20159] [Citation(s) in RCA: 152] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Thymidine phosphorylase (TP), also known as "platelet-derived endothelial cell growth factor" (PD-ECGF), is an enzyme, which is upregulated in a wide variety of solid tumors including breast and colorectal cancers. TP promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis. Elevated levels of TP are associated with tumor aggressiveness and poor prognosis. Therefore, TP inhibitors are synthesized in an attempt to prevent tumor angiogenesis and metastasis. TP is also indispensable for the activation of the extensively used 5-fluorouracil prodrug capecitabine, which is clinically used for the treatment of colon and breast cancer. Clinical trials that combine capecitabine with TP-inducing therapies (such as taxanes or radiotherapy) suggest that increasing TP expression is an adequate strategy to enhance the antitumoral efficacy of capecitabine. Thus, TP plays a dual role in cancer development and therapy: on the one hand, TP inhibitors can abrogate the tumorigenic and metastatic properties of TP; on the other, TP activity is necessary for the activation of several chemotherapeutic drugs. This duality illustrates the complexity of the role of TP in tumor progression and in the clinical response to fluoropyrimidine-based chemotherapy.
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Affiliation(s)
| | - Federico Gago
- Departamento de Farmacología, Universidad de Alcalá, 28871 Alcalá de Henares, Spain
| | - Jan Balzarini
- Rega Institute for Medical Research, K.U.Leuven, B‐3000 Leuven, Belgium
| | - Sandra Liekens
- Rega Institute for Medical Research, K.U.Leuven, B‐3000 Leuven, Belgium
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